新型四氢苯并噻唑化合物作为雄激素受体调节剂的合成与构效关系（英文）
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摘要
前列腺癌是男性最常被诊断出的癌症之一,而雄激素受体(androgen receptor,AR)是前列腺癌治疗的重要靶标。现有的AR拮抗剂在长期使用后通常由于多种原因而失效。因此,新型AR拮抗剂的开发仍具有重要的意义。一系列四氢苯并噻唑类化合物,通过α,β-环氧环己酮与适当的硫脲的缩合反应被合成。其中,多个化合物在酵母双杂交系统中表现出强于或相当于氟他胺的雄激素受体拮抗活性(IC50≤2. 48 mmol/L)。进一步的细胞活力试验表明,这些活性化合物有效地抑制了雄激素敏感的LNCa P细胞的增殖(IC50值17. 1～41. 4 mmol/L)。分子对接研究提供了化合物与受体相互作用的可能模型,较好地符合了初步的构效关系研究。总之,本文的研究证明,四氢苯并噻唑可以作为有效的AR调节剂,可能代表了一种有前景的先导化合物,有助于进一步开发出新型的更加强效的雄激素受体拮抗剂。
Prostate cancer is one of the most commonly diagnosed cancer in men,and androgen receptor( AR) is an important target for the treatment of prostate cancer. For many reasons,existing AR antagonists fail to treat prostate cancer after long-term use. Therefore,the development of novel AR antagonists is still of great significance. A series of tetrahydrobenzo [d]thiazole compounds were synthesized by condensation reaction of α,β-epoxycyclohexanones and appropriate substituted thioureas8,which were obtained from the corresponding anilines 7. Their antiandrogenic activities were tested using an yeast two-hybrid( Y2 H) system,and several compounds exhibited androgen receptor( AR)antagonistic behavior equal or stronger than that of flutamide( IC50≤ 2. 48 mmol/L). Further cell viability assay demonstrated that some active compounds effectively inhibited the proliferation of androgensensitive LNCa P cells values with IC50 values of 17. 1 ～ 41. 4 mmol/L. Molecular docking study provide a possible model of ligand receptor interactions,which was consistent with the initial structure-activity relationship( SAR) studies. Taken together,tetrahydrobenzo[d]thiazoles act as effective AR modulators may represent promising leads for further development of novel and improved AR antagonists.
Prostate cancer is one of the most commonly diagnosed cancer in men,and androgen receptor( AR) is an important target for the treatment of prostate cancer. For many reasons,existing AR antagonists fail to treat prostate cancer after long-term use. Therefore,the development of novel AR antagonists is still of great significance. A series of tetrahydrobenzo [d]thiazole compounds were synthesized by condensation reaction of α,β-epoxycyclohexanones and appropriate substituted thioureas8,which were obtained from the corresponding anilines 7. Their antiandrogenic activities were tested using an yeast two-hybrid( Y2 H) system,and several compounds exhibited androgen receptor( AR)antagonistic behavior equal or stronger than that of flutamide( IC50≤ 2. 48 mmol/L). Further cell viability assay demonstrated that some active compounds effectively inhibited the proliferation of androgensensitive LNCa P cells values with IC50 values of 17. 1 ～ 41. 4 mmol/L. Molecular docking study provide a possible model of ligand receptor interactions,which was consistent with the initial structure-activity relationship( SAR) studies. Taken together,tetrahydrobenzo[d]thiazoles act as effective AR modulators may represent promising leads for further development of novel and improved AR antagonists.
引文
[1] Jemal A,Bray F,Center MM,et al. Global cancer statistics[J]. CA Cancer J Clin,2011,61(2):69-90
[2] Siegel RL,Miller KD,Jemal A. Cancer statistics,2017[J].CA Cancer J Clin,2017,67(1):7-30
[3] Mangelsdorf DJ,Thummel C,Beato M,et al. The nuclear receptor superfamily:the second decade[J]. Cell,1995,83(6):835-839
[4] Evans RM. The steroid and thyroid hormone receptor superfamily[J]. Science,1988,240(4854):889-895
[5] Ahmed A,Ali S,Sarkar FH. Advances in androgen receptor targeted therapy for prostate cancer[J]. J Cell Physiol,2014,229(3):271-276
[6] Feldman BJ, Feldman D. The development of androgenindependent prostate cancer[J]. Nat Rev Cancer,2001,1(1):34-45
[7] Culig Z. Targeting the androgen receptor in prostate cancer[J].Expert Opin Pharmacother,2014,15(10):1427-1437
[8] Taplin ME. Androgen receptor:role and novel therapeutic prospects in prostate cancer[J]. Expert Rev Anticancer Ther,2008,8(9):1495-1508
[9] Yap TA,Zivi A,Omlin A,et al. The changing therapeutic landscape of castration-resistant prostate cancer[J]. Nat Rev Clin Oncol,2011,8(10):597-610
[10] Gleave M,Bruchovsky N,Goldenberg SL,et al. Intermittent androgen suppression for prostate cancer:rationale and clinical experience[J]. Eur Urol,1998,34 Suppl 3:37-41
[11] Albertsen PC,Hanley JA,Fine J. 20-year outcomes following conservative management of clinically localized prostate cancer[J]. JAMA,2005,293(17):2095-2101
[12] Helsen C,Van den Broeck T,Voet A,et al. Androgen receptor antagonists for prostate cancer therapy[J]. Endocr Relat Cancer,2014,21(4):T105-118
[13] Huang JK, Bartsch W, Voigt KD. Interactions of an antiandrogen(cyproterone acetate)with the androgen receptor system and its biological action in the rat ventral prostate[J]. Acta Endocrinol(Copenh),1985,109(4):569-576
[14] Sogani PC,Whitmore WF Jr. Experience with flutamide in previously untreated patients with advanced prostatic cancer[J].J Urol,1979,122(5):640-643
[15] Delaere KP,Van Thillo EL. Flutamide monotherapy as primary treatment in advanced prostatic carcinoma[J]. Semin Oncol,1991,18(5 Suppl 6):13-18
[16] Neri R,Florance K,Koziol P,et al. A biological profile of a nonsteroidal antiandrogen, Sch 13521(4'-nitro-3'trifluoromethylisobutyranilide)[J]. Endocrinology, 1972, 91(2):427-437
[17] Furr BJ. ICI 176,334:a novel non-steroidal,peripherallyselective antiandrogen[J]. Prog Clin Biol Res,1988,260:13-26
[18] Decensi AU,Boccardo F,Guarneri D,et al. Monotherapy with nilutamide, a pure nonsteroidal antiandrogen, in untreated patients with metastatic carcinoma of the prostate. The Italian Prostatic Cancer Project[J]. J Urol,1991,146(2):377-381
[19] Mc Leod DG. Antiandrogenic drugs[J]. Cancer,1993,71(3Suppl):1046-1049
[20] Otsuka T,Iguchi K,Fukami K,et al. Androgen receptor W741c and T877a mutations in Aidl cells,an androgen-independent subline of prostate cancer Lncap cells[J]. Tumour Biol,2011,32(6):1097-1102
[21] Tilley WD,Lim-Tio SS,Horsfall DJ,et al. Detection of discrete androgen receptor epitopes in prostate cancer by immunostaining:measurement by color video image analysis[J]. Cancer Res,1994,54(15):4096-4102
[22] Yuan X,Cai C,Chen S,et al. Androgen receptor functions in castration-resistant prostate cancer and mechanisms of resistance to new agents targeting the androgen axis[J]. Oncogene,2014,33(22):2815-2825
[23] Veldscholte J,Ris-Stalpers C,Kuiper GG,et al. A mutation in the ligand binding domain of the androgen receptor of human Lncap cells affects steroid binding characteristics and response to anti-androgens[J]. Biochem Biophys Res Commun,1990,173(2):534-540
[24] Hara T,Miyazaki J,Araki H,et al. Novel mutations of androgen receptor:a possible mechanism of bicalutamide withdrawal syndrome[J]. Cancer Res,2003,63(1):149-153
[25] Mukherji D,Pezaro C J,De-Bono JS. Mdv3100 for the treatment of prostate cancer[J]. Expert Opin Investig Drugs,2012,21(2):227-233
[26] Rathkopf D, Scher HI. Androgen receptor antagonists in castration-resistant prostate cancer[J]. Cancer J,2013,19(1):43-49
[27] Jung ME,Ouk S,Yoo D,et al. Structure-activity relationship for thiohydantoin androgen receptor antagonists for castrationresistant prostate cancer(CRPC)[J]. J Med Chem,2010,53(7):2779-2796
[28] Scher HI,Beer TM,Higano CS,et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer:a phase 1-2study[J]. Lancet,2010,375(9724):1437-1446
[29] Joseph JD,Lu N,Qian J,et al. A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN-509[J]. Cancer Discov,2013,3(9):1020-1029
[30] Tomasic T,Katsamakas S,Hodnik Z,et al. Discovery of 4,5,6,7-Tetrahydrobenzo[1,2-d] thiazoles as novel DNA gyrase inhibitors targeting the ATP-Binding Site[J]. J Med Chem,2015,58(14):5501-5521
[31] Zhen J, Antonio T, Jacob JC, et al. Efficacy of Hybrid Tetrahydrobenzo[d]thiazole Based Aryl Piperazines D-264 and D-301 at D2and D3receptors[J]. Neurochem Res,2016,41(1-2):328-339
[32] Lu W,Cheng F,Jiang J,et al. FXR antagonism of NSAIDs contributes to drug-induced liver injury identified by systems pharmacology approach[J]. Sci Rep,2015,5:8114
[33] Liu P, Shen H, Shao X, et al. Cheminform Abstract:Multipathways for the Synthesis of Fused Bicyclic 2-Aminothiazolyl Compounds Tuned by Ring Size[J]. Synlett,2015,46(19):2797-2801
[34] Kim J,Jung S,Park S,et al. Amino-Acid-Mediated Epoxidation ofΑ,Β-Unsaturated Ketones by Hydrogen Peroxide in Aqueous Media[J]. Tetrahedron Lett,2011,52(22):2866-2868
[35] Gietz RD, Woods RA. Transformation of yeast by lithium acetate/single-stranded carrier DNA/polyethylene glycol method[J]. Methods Enzymol,2002,350:87-96
[38] Voegel JJ,Heine MJ,Zechel C,et al. TIF2,a 160 KDa transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors[J]. EMBO J,1996,15(14):3667-3675
[39] Cao X,Jiang J,Zhang S,et al. Discovery of natural estrogen receptor modulators with structure-based virtual screening[J].Bioorg Med Chem Lett,2013,23(11):3329-3333
[40] Callaway TW,Bruchovsky N,Rennie PS,et al. Mechanisms of action of androgens and antiandrogens:effects of antiandrogens on translocation of cytoplasmic androgen receptor and nuclear abundance of dihydrotestosterone[J]. Prostate,1982,3(6):599-610
[41] Sadar MD. Small molecule inhibitors targeting the“achilles’heel”of androgen receptor activity[J]. Cancer Res,2011,71(4):1208-1213
[42] Maggiolini M,Vivacqua A,Carpino A,et al. The mutant androgen receptor T877a mediates the proliferative but not the cytotoxic dose-dependent effects of genistein and quercetin on human LNCa P prostate cancer cells[J]. Mol Pharmacol,2002,62(5):1027-1035
[2] Siegel RL,Miller KD,Jemal A. Cancer statistics,2017[J].CA Cancer J Clin,2017,67(1):7-30
[3] Mangelsdorf DJ,Thummel C,Beato M,et al. The nuclear receptor superfamily:the second decade[J]. Cell,1995,83(6):835-839
[4] Evans RM. The steroid and thyroid hormone receptor superfamily[J]. Science,1988,240(4854):889-895
[5] Ahmed A,Ali S,Sarkar FH. Advances in androgen receptor targeted therapy for prostate cancer[J]. J Cell Physiol,2014,229(3):271-276
[6] Feldman BJ, Feldman D. The development of androgenindependent prostate cancer[J]. Nat Rev Cancer,2001,1(1):34-45
[7] Culig Z. Targeting the androgen receptor in prostate cancer[J].Expert Opin Pharmacother,2014,15(10):1427-1437
[8] Taplin ME. Androgen receptor:role and novel therapeutic prospects in prostate cancer[J]. Expert Rev Anticancer Ther,2008,8(9):1495-1508
[9] Yap TA,Zivi A,Omlin A,et al. The changing therapeutic landscape of castration-resistant prostate cancer[J]. Nat Rev Clin Oncol,2011,8(10):597-610
[10] Gleave M,Bruchovsky N,Goldenberg SL,et al. Intermittent androgen suppression for prostate cancer:rationale and clinical experience[J]. Eur Urol,1998,34 Suppl 3:37-41
[11] Albertsen PC,Hanley JA,Fine J. 20-year outcomes following conservative management of clinically localized prostate cancer[J]. JAMA,2005,293(17):2095-2101
[12] Helsen C,Van den Broeck T,Voet A,et al. Androgen receptor antagonists for prostate cancer therapy[J]. Endocr Relat Cancer,2014,21(4):T105-118
[13] Huang JK, Bartsch W, Voigt KD. Interactions of an antiandrogen(cyproterone acetate)with the androgen receptor system and its biological action in the rat ventral prostate[J]. Acta Endocrinol(Copenh),1985,109(4):569-576
[14] Sogani PC,Whitmore WF Jr. Experience with flutamide in previously untreated patients with advanced prostatic cancer[J].J Urol,1979,122(5):640-643
[15] Delaere KP,Van Thillo EL. Flutamide monotherapy as primary treatment in advanced prostatic carcinoma[J]. Semin Oncol,1991,18(5 Suppl 6):13-18
[16] Neri R,Florance K,Koziol P,et al. A biological profile of a nonsteroidal antiandrogen, Sch 13521(4'-nitro-3'trifluoromethylisobutyranilide)[J]. Endocrinology, 1972, 91(2):427-437
[17] Furr BJ. ICI 176,334:a novel non-steroidal,peripherallyselective antiandrogen[J]. Prog Clin Biol Res,1988,260:13-26
[18] Decensi AU,Boccardo F,Guarneri D,et al. Monotherapy with nilutamide, a pure nonsteroidal antiandrogen, in untreated patients with metastatic carcinoma of the prostate. The Italian Prostatic Cancer Project[J]. J Urol,1991,146(2):377-381
[19] Mc Leod DG. Antiandrogenic drugs[J]. Cancer,1993,71(3Suppl):1046-1049
[20] Otsuka T,Iguchi K,Fukami K,et al. Androgen receptor W741c and T877a mutations in Aidl cells,an androgen-independent subline of prostate cancer Lncap cells[J]. Tumour Biol,2011,32(6):1097-1102
[21] Tilley WD,Lim-Tio SS,Horsfall DJ,et al. Detection of discrete androgen receptor epitopes in prostate cancer by immunostaining:measurement by color video image analysis[J]. Cancer Res,1994,54(15):4096-4102
[22] Yuan X,Cai C,Chen S,et al. Androgen receptor functions in castration-resistant prostate cancer and mechanisms of resistance to new agents targeting the androgen axis[J]. Oncogene,2014,33(22):2815-2825
[23] Veldscholte J,Ris-Stalpers C,Kuiper GG,et al. A mutation in the ligand binding domain of the androgen receptor of human Lncap cells affects steroid binding characteristics and response to anti-androgens[J]. Biochem Biophys Res Commun,1990,173(2):534-540
[24] Hara T,Miyazaki J,Araki H,et al. Novel mutations of androgen receptor:a possible mechanism of bicalutamide withdrawal syndrome[J]. Cancer Res,2003,63(1):149-153
[25] Mukherji D,Pezaro C J,De-Bono JS. Mdv3100 for the treatment of prostate cancer[J]. Expert Opin Investig Drugs,2012,21(2):227-233
[26] Rathkopf D, Scher HI. Androgen receptor antagonists in castration-resistant prostate cancer[J]. Cancer J,2013,19(1):43-49
[27] Jung ME,Ouk S,Yoo D,et al. Structure-activity relationship for thiohydantoin androgen receptor antagonists for castrationresistant prostate cancer(CRPC)[J]. J Med Chem,2010,53(7):2779-2796
[28] Scher HI,Beer TM,Higano CS,et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer:a phase 1-2study[J]. Lancet,2010,375(9724):1437-1446
[29] Joseph JD,Lu N,Qian J,et al. A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN-509[J]. Cancer Discov,2013,3(9):1020-1029
[30] Tomasic T,Katsamakas S,Hodnik Z,et al. Discovery of 4,5,6,7-Tetrahydrobenzo[1,2-d] thiazoles as novel DNA gyrase inhibitors targeting the ATP-Binding Site[J]. J Med Chem,2015,58(14):5501-5521
[31] Zhen J, Antonio T, Jacob JC, et al. Efficacy of Hybrid Tetrahydrobenzo[d]thiazole Based Aryl Piperazines D-264 and D-301 at D2and D3receptors[J]. Neurochem Res,2016,41(1-2):328-339
[32] Lu W,Cheng F,Jiang J,et al. FXR antagonism of NSAIDs contributes to drug-induced liver injury identified by systems pharmacology approach[J]. Sci Rep,2015,5:8114
[33] Liu P, Shen H, Shao X, et al. Cheminform Abstract:Multipathways for the Synthesis of Fused Bicyclic 2-Aminothiazolyl Compounds Tuned by Ring Size[J]. Synlett,2015,46(19):2797-2801
[34] Kim J,Jung S,Park S,et al. Amino-Acid-Mediated Epoxidation ofΑ,Β-Unsaturated Ketones by Hydrogen Peroxide in Aqueous Media[J]. Tetrahedron Lett,2011,52(22):2866-2868
[35] Gietz RD, Woods RA. Transformation of yeast by lithium acetate/single-stranded carrier DNA/polyethylene glycol method[J]. Methods Enzymol,2002,350:87-96
[38] Voegel JJ,Heine MJ,Zechel C,et al. TIF2,a 160 KDa transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors[J]. EMBO J,1996,15(14):3667-3675
[39] Cao X,Jiang J,Zhang S,et al. Discovery of natural estrogen receptor modulators with structure-based virtual screening[J].Bioorg Med Chem Lett,2013,23(11):3329-3333
[40] Callaway TW,Bruchovsky N,Rennie PS,et al. Mechanisms of action of androgens and antiandrogens:effects of antiandrogens on translocation of cytoplasmic androgen receptor and nuclear abundance of dihydrotestosterone[J]. Prostate,1982,3(6):599-610
[41] Sadar MD. Small molecule inhibitors targeting the“achilles’heel”of androgen receptor activity[J]. Cancer Res,2011,71(4):1208-1213
[42] Maggiolini M,Vivacqua A,Carpino A,et al. The mutant androgen receptor T877a mediates the proliferative but not the cytotoxic dose-dependent effects of genistein and quercetin on human LNCa P prostate cancer cells[J]. Mol Pharmacol,2002,62(5):1027-1035